Hepatitis C virus (HCV) infection is a major cause of liver disease throughout the world. Existing therapies are suboptimal and the search for alternative therapies is imperative. Recent years have seen a tremendous increase in efforts to identify more effective therapies against HCV. These efforts have been greatly facilitated by sub-genomic HCV replicon systems that efficiently replicate in cell culture. However, despite all the benefits of these replicon systems, the lack of an infectious HCV system in cell culture is still an impediment to all aspects of HCV studies, particularly the development of HCV anti-viral therapies. The recent development of an HCV clone that is infectious in cell culture (termed HCVcc) can directly address these shortcomings. The focus of this proposal is to develop the HCVcc system as a more useful tool for drug development. This includes identifying culture methods for increasing HCVcc titer, developing HCVcc genotypes relevant to the dominant drug development target, and facilitating drug cross-resistance studies by generating mutant infectious HCV viruses that harbor drug resistance mutations reported against experimental anti-HCV compounds presently being developed and evaluated. Results obtained here will not only directly benefit drug development efforts, but will also provide critical information and reagents to a rapidly-developing field of basic research. [unreadable] [unreadable] Infectious HCV for drug discovery. [unreadable] [unreadable] [unreadable]